The present invention relates to a novel compound and further relates to pharmaceutical compositions which contain the novel compound of the present invention. The present invention also related to a method of preparing the novel compound of the present invention. Finally, the present invention relates to a method for treating or preventing conditions characterized by abnormal calcium and phosphate metabolism by utilizing a compound or pharmaceutical composition of the present invention.
A number of pathological conditions which can afflict humans and lower animals involve abnormal calcium and phosphate metabolism. Such conditions may be divided into two broad categories:                (1) Conditions which are characterized by anomalous mobilization of calcium and phosphate leading to general or specific bone loss, or excessively high calcium and phosphate levels in the fluids of the body, such as osteoporosis, osteolytic bone metastasis, and Paget's Disease. Such conditions are sometimes referred to herein as pathological hard tissue demineralizations.        (2) Conditions which cause or result from deposition of calcium and phosphate anomalously in the body, such as arthritis. These conditions are sometimes referred to herein as pathological calcifications.        
A variety of polyphosphonic acid derivatives have been proposed for use in the treatment and prophylaxis of conditions involving abnormal calcium and phosphate metabolism. For example, U.S. Pat. No. 3,683,080 discloses compositions containing polyphosphonates, in particular diphosphonates, and their use in inhibiting anomolous deposition and mobilization of calcium phosphate in animal tissue; U.S. Pat. No. 4,230,700 discloses composition containing certain phosphonate compounds (e.g., cycloalkyl-substituted hydroxyethane diphosphonates) in combination with vitamin D-like compounds useful in inhibiting mobilization of calcium phosphate in animal tissue; U.S. Pat. No. 3,988,443 discloses azacycloalkane-2,2-diphosphonate compound said to be useful as sequestering agents and as agents in the treatment of conditions related to the abnormal deposition or dissolution of difficulty soluble calcium salts in the animal body; and European Patent Publication No. 189,662 which discloses various specific cyclic diphosphonate compounds said to be useful as sequestering agents or as agents in the treatment of conditions characterized by abnormal calcium and phosphate metabolism. The disclosures of all these patents and applications are incorporated herein by reference in their entirety.
In spite of this and much other research into the use of diphosphonates to treat bone-metabolism conditions, there continues to be a need for new bone-active agents. The object of the present invention is therefore to provide new bone-active diphosphonate compounds having relatively high potency for inhibiting bone re-sorption. Furthermore, an object of the present invention is to provide new bone-active diphosphonate compounds with low toxicity and favorable therapeutic indices. It is a further object of the present invention to provide pharmaceutical compositions useful for the treatment and prophylaxis of abnormal calcium and phosphate metabolism. In addition, it is an object of the present invention to provide methods for treating or preventing conditions characterized by abnormal calcium and phosphate metabolism in humans or lower animals.
U.S. Pat. No. 4,868,164 discloses compounds having nitrogen-containing, saturated bicyclic cyclopentane-fused rings which are germinally disubstituted with phosphonate groups. Preferred are substituted or unsubstituted octahydro pyrindine diphosphonate compounds, especially substituted or unsubstituted octahydro 1-pyrindine-6,6-diphosphonic acid compounds, and the pharmaceutically-acceptable salts and esters thereof. The '164 patent further discloses pharmaceutical compositions containing a safe and effective amount of said compounds, and a pharmaceutically-acceptable carrier.
The racemic mixture of the 1R,6S and 1S,6R isomers is the subject of U.S. Pat. No. 4,868,164. The '164 patent describes the racemic mixture and specifically the cis-ring juncture of the other enantiomer, (1S,6R). The racemic mixture and the 1S,6R enantiomer were also described in a paper published in 1990. (Ebetino et al., “Studies on a Potent New Antiresorptive Bisphosphonate Class: Cis- Octahydro-1-pyrindine-6,6-Bisphosphonic Acid, Ne-58025 and its Analogues” In: Osteoporosis 1990, 3, 3rd International Symposium on Osteoporosis, Copenhagen, Denmark, Oct. 14-20, 1990, edited by C. Christiansen and K. Overgaard, Handelstrykkeriet Aalborg Aps, Aalborg, Denmark, 1990, p. 1344-1346).
Farnesyl pyrophosphate synthase (FPPS) is a key regulatory enzyme in the mevalonate pathway. This pathway, ubiquitous in mammalian cells, provides essential lipid molecules, such as cholesterol and isoprenoids, with the latter necessary for posttranslational prenylation of small GTPases. The blockade of this pathway is a concept that has found widespread clinical use, with statins as drugs that inhibit hydroxymethylglutaryl-CoA reductase and reduce cholesterol biosynthesis, and nitrogen-containing bisphosphonates (N-BPs) as drugs for osteoporosis therapy that target FPPS and inhibit protein prenylation. In the case of N-BPs, the unique bone-targeting pharmacokinetic properties of these compounds cause selective inhibition of FPPS and loss of prenylated proteins in osteoclasts, thereby inhibiting the bone-destroying function of these cells.
The inventors herein find that a specific isomer, (1R,6S)-2-Azabicyclo-[4.3.0]nonane-8,8-diphosphonic acid, shows at least an order of magnitude more activity (for example, IC50=15 nM) than its 1S,6R enantiomer, (for example, IC50=359 nM), in the farnesyl pyrophosphate synthase (FPPS) inhibition assay.